Evaluation of Novel Acute Urinary Rat Kidney Toxicity Biomarker for Subacute Toxicity Studies in Preclinical Trials

被引:60
作者
Fuchs, Tobias Christian [1 ]
Frick, Katharina [2 ]
Emde, Barbara [1 ]
Czasch, Stephanie [1 ]
von Landenberg, Friedrich [1 ]
Hewitt, Philip [1 ]
机构
[1] Merck Serono, Merck KGaA, Toxicol, D-64293 Darmstadt, Germany
[2] Mannheim Univ Appl Sci, Mannheim, Germany
关键词
nephrotoxicity; urinary biomarkers; multiplexed analyte profiling; cisplatin; vancomycin; puromycin; 28-day toxicity study; ENDOTHELIAL GROWTH-FACTOR; GELATINASE-ASSOCIATED LIPOCALIN; GLUTATHIONE S-TRANSFERASES; INJURY MOLECULE-1; INDUCED NEPHROTOXICITY; CYSTATIN-C; OSTEOPONTIN EXPRESSION; TISSUE INHIBITOR; RENAL INJURY; MARKER;
D O I
10.1177/0192623312444618
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Novel urinary protein biomarkers for the detection of acute renal damage, recently accepted by the U.S. Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency (Japan), now have to be validated in practice. Limited data regarding the performance of these acute markers after subacute or subchronic treatment are publicly available. To increase the area of applicability of these markers, it is important to evaluate the ability to detect them after 28 days of treatment or even longer. Wistar rats were treated with three doses of cisplatin, vancomycin, or puromycin to induce renal damage. Twelve candidate proteins were measured by Luminex xMAP-based WideScreen assays, MesoScale Discovery-based MULTI-SPOT technology, or RENA-strip dipstick assay after 28 days. Treatment with all three model compounds resulted in a dose-dependent increase in urinary biomarkers, specific for the observed areas within the nephron, determined histopathologically. The most promising biomarkers in this study were NGAL, Kim-1, osteopontin, clusterin, RPA-1, and GSTYb1, detected by multiplexing technologies. The RENA-strip dipstick assay delivered good diagnostic results for vancomycin-treated but not for cisplatin- or puromycin-treated rats. Taken together, the data show that these new biomarkers are robust and measurable for longer term studies to predict different types of kidney toxicities.
引用
收藏
页码:1031 / 1048
页数:18
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